The major goal of this R21 Exploratory/Developmental grant proposal is to develop a new model in which the morphological correlates of synaptic strengthening induced by learning can be studied. Learning a new forelimb reach and grasp task has been shown to leave a trace in the forelimb area of the primary motor cortex (MI): synapses are strengthened in layer II/III intracortical horizontal connections in the hemisphere controlling the trained forelimb. This proposal will test the hypothesis that changes in synaptic morphology and dynamics underlie this learning-induced synaptic strengthening in the adult MI. Layer II/III neurons in MI will be labeled by in vivo viral injections. The first aim will determine changes in spine density and morphology in slices from trained rats and correlate them to synaptic strength changes and long-term potentiation. The second aim will determine changes in dynamics of dendritic spines by two photon repeated In vivo imaging of MI neurons at different time points during skill learning and consolidation. This model will link a quantifiable behavior (forelimb reach and grasp task) with changes in synaptic strength, and changes in morphology and dynamics of synaptic structures. The strength and uniqueness of the proposed project is the combination of powerful two-photon live imaging techniques with a model for studying learning-induced changes in synaptic efficacy. If successful, this exploratory/developmental grant (R21) will be expanded to a five-year proposal to study the molecular basis of learning-induced morphological changes in synaptic strength and morphology. Information gained from these studies will be crucial in ultimately understanding the mechanisms of memory loss during pathological conditions and aging. [unreadable] [unreadable]